It is postulated by this investigator that the progressive neurodegeneration occurring in AD is a result, at least in part, of the neurotoxic properties of the amyloid beta protein (Abeta). The neurotoxic effects of Abeta are mediated by free radicals and depend on the secondary structure of the protein and or its polymerization into fibrils. These structural changes also determine its resistance to proteolysis, rate of amyloid formation, and resistance to clearance. Since these feature are considered key to amyloid accumulation, mechanisms and factors implicated in fibrillogenesis and protease resistance are considered important issues in AD. Recent studies by the P.I. have shown that melatonin has strong cytoprotective properties against Abeta toxicity in vitro. In addition to protecting against oxidative stress, it also appears to inhibit the progressive formation of beta-sheet structures of Abeta as well as polymerization into fibrils. Because melatonin has less side effects than many other agents and the fact that it enters the nervous system has encouraged the P.I. to propose studies to test it experimentally. In this grant, the P.I. proposes to utilize a transgenic mouse model 1) to determine whether the in vitro properties of PBN (a free radical scavenger) and melatonin (anti-oxidant, anti-amyloid) can be verified in vivo. and 2) to further characterize the biochemical and neuropathological alterations related to oxidative stress in order to evalulate the effects of melatonin and PBN.